On August 5, 2022 The European Organisation for Research and Treatment of Cancer (EORTC) reported that it has finished patient recruitment for the EORTC-1612-MG trial in patients with unresected or metastatic melanoma (Press release, EORTC, AUG 5, 2022, View Source [SID1234617692]). The randomised trial will study the effect of combined targeted therapy (encorafenib and binimetinib) followed by combined immunotherapy (ipilimumab and nivolumab) as compared to immediate combined immunotherapy, in patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

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Systemic therapy options for metastatic melanoma currently depend on whether the patient’s tumour expresses the so-called BRAF mutation. Activating mutations in the BRAF gene (a protein kinase) occur in 40-60% of patients, the most common mutations being V600E, followed by V600K. In recent years, the approval of immunomodulatory agents and targeted agents for treatment of advanced or metastatic melanoma has dramatically changed the landscape and is leading to a potential broad range of applications for combination therapies.

To date, there is no consensus on the optimal first line treatment for patients with BRAF mutant metastatic melanoma.

Evidence suggests that targeted agents can provide not only additive effects to immunotherapy but can also sensitise the tumour cells to immune attacks (by increasing antigen expression) and improve the effector function of immune cells. Pre-clinical data support the rationale for intermittent regimens with BRAF inhibitors, showing that the development of resistance could be delayed with intermittent therapy. The hypothesis is that a sequential approach could merge the high response rate of target therapy with the peculiarity of immunotherapy to achieve long-term durable responses, prior to secondary resistance to the targeted therapy occurring.

Recruitment to the EORTC-1612-MG trial started in November 2018. Completion of recruitment marks a crucial milestone for the trial.

‘I would like to sincerely thank all the persons who made this study possible in spite of the difficulties we went through in this troubled period. We will finally soon be in a position to answer the important questions that we wanted to address with this study’, says Professor Caroline Robert from the Gustave Roussy Cancer Institute, Villejuif, France and Coordinator of this trial for the EORTC Melanoma Group.

About the study
This is a multicentre, 2-arm open-label, randomised comparative phase II study. Its primary objective is to prospectively assess whether a sequential treatment approach with an induction period of 12 weeks with chemotherapy drugs encorafenib + binimetinib, followed by an immunotherapy combination with immunomodulatory agents nivolumab + ipilimumab, improves Progression Free Survival (PFS) compared to a nivolumab + ipilimumab immunotherapy combination alone as first line treatment, in patients with BRAF V600 mutation–positive unresectable or metastatic melanoma.

A total of 270 patients with unresectable or metastatic (stage IV) (as per AJCC Cancer Staging Manual, 7th edition) melanoma were randomised to receive either one of the two treatments:

Treatment arm A: nivolumab 3 mg/kg once every 3 weeks + ipilimumab 1 mg/kg once every 3 weeks or 4 infusions followed by nivolumab 480 mg intravenously once every 4 weeks until completion of 2 years total treatment or disease progression. Then treatment will be left at the investigator choice and continued until the second progression.

Treatment arm B: encorafenib 450 mg once a day + binimetinib 45 mg twice a day orally for 12 weeks followed, after a week of pause, by nivolumab 3 mg/kg once every 3 weeks + ipilimumab 1 mg/kg once every 3 weeks for 4 infusions, followed by nivolumab 480 mg intravenously once every 4 weeks until completion of 2 years total treatment or disease progression. Then patients will be rechallenged with encorafenib 450 mg once a day + binimetinib 45 mg twice a day orally continuously until the second progression.

This is an academic trial supported by the EORTC Melanoma Group, and a restricted educational grant from Pierre Fabre and Bristol Myers Squibb, who supply encorafenib & binimetinib and nivolumab & ipilimumab, respectively, for the duration of the trial.

First results from the trial are expected around mid-2023.

About Melanoma
Melanoma is the deadliest form of skin cancer. Historically, melanoma was a rare cancer, but in the last 50 years its incidence has risen faster than almost any other cancer [1] making it the 19th most commonly occurring cancer worldwide,[2] with over 320,000 new cases and over 55,000 deaths, in 2020.[3] After Australia and New Zealand, European countries have highest rates of melanoma incidence. According to GLOBOCAN, in Europe there are approximately 144.000 cases diagnosed per year and 27.000 deaths related.[4] By 2025, the number of cases is expected to increase to over 340,000.[5] Approximately half of the cases diagnosed have BRAF mutations, a key target in the treatment of metastatic melanoma.[6-8]

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours.[9] Starting from pigment-producing cells (melanocytes) in the skin, melanoma spreads to other parts of the body through metastasis.

Before the development of immune checkpoint inhibitors and anti-BRAF-targeted therapy, patients with metastatic melanoma had a median OS of less than 12 months. Both targeted therapy (anti-BRAF + anti-MEK) [11] and immunotherapy (anti-PD1 +/- anti-CTLA-4) have significantly prolonged the OS of patients with BRAF mutant metastatic melanoma.[11]

Matthews NH, Li WQ, Qureshi AA, et al. Epidemiology of Melanoma. In: Ward WH, Farma JM, editors. Cutaneous Melanoma: Etiology and Therapy [Internet]. Brisbane (AU): Codon Publications; 2017 Dec 21. Chapter 1. Available from: View Source doi: 10.15586/codon.cutaneousmelanoma.2017.ch1
WCRF International, Cancer trends – Skin cancer statistics; View Source
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 2021;71:209–249. View Source
Melanoma Patient Network Europe, Melanoma – the facts. View Source
Melanoma UK. 2020 Melanoma Skin Cancer Report. View Source
American Cancer Society. What Causes Melanoma Skin Cancer. View Source
International Agency for Research on Cancer. Melanoma of skin. View Source
Klein O, et al. Eur J Cancer 2013;49:1073–1079.
2016;63(4):510-7. doi: 10.4149/neo_2016_40
Zeynep Eroglu, Antoni Ribas. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol. 2016; 8(1): 48–56. View Source
Anand Rotte. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. Journal of Experimental & Clinical Cancer Research 2019; 38:255. View Source
About the EORTC Melanoma Group
The Melanoma Group aims to improve the clinical care of patients suffering with cutaneous, mucosal, or ocular melanoma, and to increase knowledge about melanoma acquisition and progression. Group sub-committees focus on topics including epidemiology, early-stage melanoma, surgery, pathology, and systemic therapy (adjuvant and for advanced disease).

On August 5, 2022 Delcath Systems, Inc. (Nasdaq: DCTH), an interventional oncology company focused on the treatment of primary and metastatic cancers of the liver, reported the publication of a retrospective analysis of patients who underwent a percutaneous hepatic perfusion procedure (PHP) with CHEMOSAT at three European centers, one in the Netherlands and two in Germany, between February 2014 and December 2019 (Press release, Delcath Systems, AUG 5, 2022, View Source [SID1234617691]). The study involved 101 patients who completed a minimum of one PHP procedure for the treatment of unresectable uveal melanoma (UM) liver metastases.

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The study, Predictive Parameters in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan for Unresectable Liver Metastases from Uveal Melanoma: A Retrospective Pooled Analysis, by Dr. T. M. L. Tong, et al,, included a total of 212 PHP procedures for the 101 patients included in the study. Of the 101 patients, 66 received PHP as first line treatment and 33 had received prior therapy (status of 2 patients was unknown). Approximately 50% of patients had greater than 9 metastases. Seventy-seven patients underwent at least two procedures and 25 patients received more than two PHP procedures. After a median follow-up time of 15 months, a complete response (CR) was reported in five (5.0%) patients; partial response (PR) in 55 (54.5%), and stable disease (SD) in 30 (29.7%), resulting in an objective response rate (ORR) of 59.4% and a disease control rate (DCR) of 89.1%.

The median progression-free survival (PFS), liver progression-free survival (LPFS), and overall survival (OS) were 9.0 months (95% CI 7.7 -10.3); 11.0 months (95% CI 9.0 – 13.0); and 20.0 months (95% CI 13.7 – 26.3), respectively. Twelve patients who were lost to follow-up were censored in the survival analyses. The study also found statistically significant differences in median PFS, median LPFS, and OS between patients who had CR, PR, or SD; and patients with progressive disease (PD). For example, for patients with CR or PR the median OS was 27 months (95% CI 17.5 – 36.5); for patients with SD the median OS was 21 months (95% CI 11.2 – 30.8); and 8 months (95% CI 5.7 – 10.3) for patients with PD.

Although the study did not find a statistically significant difference in either median PFS and LPFS for patients treated with two or more PHP procedures compared to patients treated with one PHP procedures, the study did find a statistically significant difference in OS (20 months vs. 8 months) for patients who had two or more PHP procedures compared to patients who were treated with one PHP procedure.

The safety analysis was conducted on the first treatment cycle (183 PHP procedures). The most common adverse events were hematological toxicities which were grade 1/2 and self- limiting in the majority of patients and consistent with previous reports on PHP. Other adverse events were thromboembolic in nature. The mortality rate was 1.1% within 30 days after PHP.

"Delcath welcomes this publication and believes its results provide healthcare professionals with further evidence of Chemosat’s utility in patients suffering from metastatic uveal melanoma," said Johnny John, MD, Delcath’s Senior Vice President of Clinical Operations and Medical Affairs. "We look forward to resubmitting the NDA for Hepzato Kit, the combination of the Chemosat device packaged with melphalan, to FDA by the end of the third quarter."

On August 5, 2022 Celyad Oncology SA (Euronext & Nasdaq: CYAD) (the "Company"), a clinical-stage biotechnology company focused on the discovery and development of chimeric antigen receptor T cell (CAR T) therapies for cancer, reported an update on its financial results and recent business developments for the first half ended June 30, 2022 (Press release, Celyad, AUG 5, 2022, View Source [SID1234617690]).

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"As the Company continues to evolve, we are excited about a renewed focus on additional value drivers for Celyad Oncology. Importantly, with our world-class intellectual property focused on allogeneic CAR T technology, we have multiple opportunities for partnerships with peers in the industry," commented Michel Lussier, interim Chief Executive Officer of Celyad Oncology. "We also were proud to recently announce that the FDA lifted the clinical hold on our CYAD-101 program. In addition, we look forward to the upcoming data read out for CYAD-211 in the second half of 2022. We are truly ushering in a new chapter for Celyad Oncology by unlocking the potential of not only our product candidates, but also our portfolio of IP, technology, and overall expertise in cell therapy."

Second Quarter 2022 and Recent Business Highlights

The Board of Directors named Hilde Windels as Chair of the Board of Directors
Michel Lussier named Interim Chief Executive Officer of the Company
Pipeline and Business Updates

CYAD-211 – Allogeneic shRNA-based, anti-BCMA CAR T for r/r MM

CYAD-211 is an investigational, short hairpin RNA (shRNA)-based allogeneic CAR T candidate for the treatment of r/r MM. CYAD-211 is engineered to co-express a B cell maturation antigen (BCMA) targeting CAR and a single shRNA, which interferes with the expression of the CD3ζ component of the T-cell receptor (TCR) complex.

Preliminary data reported in December 2021 from the dose-escalation segment of the IMMUNICY-1 Phase 1 trial evaluating CYAD-211 following cyclophosphamide/fludarabine (CyFlu) preconditioning chemotherapy in patients with r/r MM showed evidence of clinical activity with a good tolerability profile including no evidence of Graft versus Host Disease. In addition, all patients in the trial had detectable CYAD-211 cells in the peripheral blood.
Enrollment is currently ongoing in the IMMUNICY-1 Phase 1 trial to evaluate enhanced lymphodepletion (eLD) and increased CYAD-211 doses with the aim to improve cell persistence and potentially maximize the clinical benefit of CYAD-211. The IMMUNICY-1 protocol also allows for CYAD-211 redosing in certain patients.
Additional data updates from the eLD cohorts of the Phase 1 IMMUNICY-1 trial of CYAD-211 for r/r MM are expected during second half of 2022.
CYAD-101 – Allogeneic TIM-based NKG2D CAR T for mCRC

CYAD-101 is an investigational, non-gene edited, allogeneic CAR T candidate engineered to co-expresses the TIM peptide alongside a CAR based on NKG2D, a receptor expressed on natural killer (NK) and T cells, that binds to eight stress-induced ligands.

In June 2022 we submitted our complete response to the clinical hold of the CYAD-101-002 phase 1b trial to the FDA stating our intent to amend the eligibility criteria to exclude patients who have bilateral lung metastases and patients who have received treatment with epidermal growth factor receptor (EGFR) targeting monoclonal antibodies within the previous 9 months prior to trial recruitment. In July 2022, based on that complete response, we received notification that the FDA lifted the clinical hold on the CYAD-101-002 phase 1b trial
shARC Platform

Discovery research continues on programs focused on the co-expression of Interleukin-18 in conjunction with our short hairpin RNA shRNA technology platform, also known as our shARC (shRNA Armored CAR) franchise, with a focus on the development of next-generation, allogeneic CAR T candidates.

CYAD-02 – Autologous NKG2D CAR-T for r/r AML and MDS

CYAD-02 is an investigational, autologous CAR T therapy that co-expresses both the NKG2D CAR and a single shRNA targeting the NKG2D ligands MICA/MICB on the CAR T cells.

In December 2021, the Company presented clinical results from the dose-escalation CYCLE-1 Phase 1 trial evaluating CYAD-02 for the treatment of r/r acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data from the trial showed that a single shRNA can target two independent genes (MICA/MICB) to enhance the phenotype of the CAR T cells. In addition, the dual knockdown showed a positive contribution to the initial clinical activity of CYAD-02 as well as a trend towards increased engraftment and persistence compared to the first-generation, autologous NKG2D receptor CAR T.
The Company continues to explore potential partnership opportunities for the future development of CYAD-02.
Strategic Focus on Intellectual Property

The Company maintains a robust intellectual property portfolio within the landscape of CAR T, including twelve foundational U.S.

patents associated with allogeneic CAR T for the treatment of cancer as well as patents for NKG2D receptor-based cell therapies. We believe these patents provide an avenue for the Company to develop its own programs as well as to seek potential partnership opportunities.

First Half 2022 Financial Results

Key financial figures for the first half of 2022, compared with the first half of 2021 and full year 2021, are summarized below:

Research and Development expenses were €10.5 million for the first half of 2022, compared to €10.0 million for the first half of 2021. The €0.5 million increase was mainly driven by intellectual property filing and maintenance fees to strengthen intellectual property prosecution and the increase of employee expenses mainly related to the full expense impact of the employees recruited during 2021 to support the Group’s preclinical and clinical programs, employee turnover and management changes, both of which were partially offset by the decrease in clinical activities resulting from the Phase 1b CYAD-101-002 (KEYNOTE-B79) trial which was on clinical hold during the second quarter of 2022.

General and Administrative expenses were €6.2 million for the first half of 2022, compared to €4.8 million for the first half of 2021. This increase is primarily attributable to an increase in insurance costs for the period, combined with an increase in employee expenses mainly related to management changes through the six-month period ended June 30, 2022.

A fair value adjustment of €1.1 million (non-cash income) related to the reassessment of the contingent consideration and other financial liabilities associated with the advancement of the Company’s NKG2D-based CAR T candidates as of June 30, 2022, required by International Financial Reporting Standards (IFRS), was mainly driven by the updated assumptions on projected revenue associated with the Company’s CYAD-101 program, for which the timing of the potential commercialization has been delayed by one year. Additionally, the addressable patient population for CYAD-101 has been reduced based on recent safety findings from the CYAD-101-002 Phase 1b trial. The fair value adjustment was also driven by updated assumptions to discount rate and revaluation of the U.S. dollar foreign exchange rate.

The Company also posted €1.6 million in net other income for the first half of 2022, compared to a net other income of €1.8 million for the first half of 2021. Other income for the first half of 2022 is primarily due to grant income from the Walloon Region of €1.4 million.

Net loss for the first half of 2022 was €14.1 million, or € (0.62) per share, compared to a net loss of €14.9 million, or € (1.02) per share, for the first half of 2021.

Net cash used in operations was €16.3 million for the first half of 2022, compared to €12.2 million for the first half of 2021.

As of June 30, 2022, the Company had cash and cash equivalents of €14.4 million ($15.0 million).

As of June 30, 2022, the total number of basic shares outstanding were 22.6 million similar to December 31, 2021.

Celyad Oncology First Half 2022 Conference Call Details

The conference call will be webcast live and archived within the "Events" section of the Celyad Oncology website.

On August 5, 2022 Cellectar Biosciences, Inc. (NASDAQ: CLRB), a late-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted treatments for cancer, reported financial results for the second quarter ended June 30, 2022 (Press release, Cellectar Biosciences, AUG 5, 2022, View Source [SID1234617689]).

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"During the second quarter, iopofosine passed an important milestone as an independent data monitoring committee completed a futility/efficacy assessment and unanimously recommended continuation of our pivotal Phase 2B trial in Waldenstrom’s macroglobulinemia (WM)," said James Caruso, president and CEO of Cellectar. "This global trial includes participation from leading institutions and world-renowned WM thought leadership, and we are excited by the active engagement of our investigators." Mr. Caruso continued, "We also look forward to providing data from our phase 2a multiple myeloma trial and our phase 1 pediatric trial for malignant brain tumors and sarcomas in the second half of 2022."

Second Quarter 2022 Financial Highlights

Cash and Cash Equivalents: As of June 30, 2022, the company had cash and cash equivalents of $24.8 million, compared to $35.7 million as of December 31, 2021. Net cash used in operating activities during the six months ended June 30, 2022 was approximately $10.8 million. The company believes its cash on hand is adequate to fund basic budgeted operations into the third quarter of 2023.

Research and Development Expense: R&D expense for the three months ended June 30, 2022 was approximately $4.5 million, which was relatively consistent when compared to approximately $4.6 million for the three months ended June 30, 2021. For the six months ended June 30, 2022, R&D expense was approximately $8.4 million, while the comparable period in 2021 was $9.3 million. The reduction in the six month period was due primarily to the timing of activities related to our ongoing WM pivotal trial as trial initiation costs were higher in the prior year.

General and Administrative Expense: G&A expense for the three months ended June 30, 2022 was $2.9 million, compared to $1.4 million for the same period in 2021. G&A expense in the six months ended June 30, 2022 was approximately $5.2 million, as compared to approximately $3.1 million in the prior year. These increases were driven largely by increased professional fees and personnel costs.

Net Loss: The net loss attributable to common stockholders for the quarter ended June 30, 2022 was ($7.4) million, or ($1.22) per share, compared to ($6.0) million, or ($1.14) per share, in the quarter ended June 30, 2021, while the loss attributable to common stockholders in the first half of 2022 was ($13.6) million, or ($2.22) per share, compared to ($12.4) million, or ($2.45) per share for the first half of 2021.

On August 5, 2022 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a late clinical stage biopharmaceutical company focused on helping patients fight cancer with oncolytic viral immunotherapies, reported financial results for the second quarter ended June 30, 2022 and provided a corporate update (Press release, Candel Therapeutics, AUG 5, 2022, View Source [SID1234617688]).

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"Candel remains on track to achieve several milestones in the second half of 2022," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel. "We are encouraged by the initial phase 2 clinical trial data for CAN-2409 in non-small cell lung cancer presented in June at ASCO (Free ASCO Whitepaper). The data presented at ASCO (Free ASCO Whitepaper) showed an 87.5 percent disease control rate in heavily pretreated patients whose cancer was progressing on PD-1 agents at clinical trial entry. In the second half of this year, we are planning for multiple inflection points, including updated clinical data from the phase 2 lung cancer clinical trial, initiation of a phase 3 clinical trial in high-grade glioma, and we will present initial data from our enLIGHTEN Discovery Platform. I am thrilled to see the rapid progress the Candel team continues to make on the discovery and development of our oncolytic viral immunotherapies for patients with cancer."

Second Quarter 2022 & Recent Highlights

Presented initial data on its open-label phase 2 clinical trial of CAN-2409 in combination with anti-PD-1 or PD-L1 targeting agents in patients with stage III/IV non-small cell lung cancer (NSCLC) in June 2022.
The data showed cytotoxic T cell response and a disease control rate of 87.5 percent achieved in patients whose cancer was progressing on anti-PD-1 therapy at clinical trial entry.
These findings were presented by co-principal investigator Charu Aggarwal, MD, MPH, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.
In addition to the ASCO (Free ASCO Whitepaper) poster session, the Company hosted a discussion with key experts Roy Herbst, MD, PhD, and Daniel Sterman, MD, to review these initial data.
The Company appointed three new members to its Board of Directors: Gary Nabel, MD, PhD, renowned virologist and immunologist; Joseph Papa, prominent business leader; and Renee Gaeta, strategic financial expert. Effective August 8, 2022, these new members will replace current Board members: Alan E. Smith, PhD, Shaan Ghandi, MD, D.Phil, and Udi Meirav, PhD, maintaining Candel’s nine-seat Board.
Key Upcoming Milestones

In the fourth quarter of 2022, the Company expects to present new data from three clinical trials:
A phase 1b clinical trial of CAN-2409 in combination with nivolumab (Opdivo) combined with standard of care in first line treatment in patients with high-grade glioma.
A phase 1 clinical trial of CAN-3110 in patients with recurrent high-grade glioma.
A phase 2 clinical trial of CAN-2409 in combination with anti-PD-1 or PD-L1 agents in patients with stage III/IV NSCLC.
The Company anticipates initiating a phase 3 clinical trial evaluating CAN-2409 in patients with high-grade glioma in the third quarter of 2022.
The Company also plans to debut initial data from its new discovery platform, enLIGHTEN, in the fourth quarter of 2022.
Financial Results for the Quarter Ended June 30, 2022

Cash Position: Cash and cash equivalents as of June 30, 2022 were $86.8 million compared to $82.6 million as of December 31, 2021. The net increase was due to receipt of $20.0 million from a term loan with Silicon Valley Bank in February 2022, offset by costs to fund operating activities and the purchase of fixed assets. Based on current plans and assumptions, the Company expects that its existing cash and cash equivalents will be sufficient to fund its operations into the first quarter of 2024.

Research and Development Expenses: Research and development expenses were $5.0 million and $10.4 million for the three- and six-month period ended June 30, 2022 compared to $3.3 million and $6.0 million for the comparable periods in 2021. The increase was primarily due to personnel-related costs for additional headcount, as well as operating expenses related to the conduct of five ongoing clinical studies, the expected initiation of a phase 3 clinical study, and the expansion of manufacturing capabilities. Excluding stock-based compensation expense of $57,000 for the three months ended June 30, 2022 and $199,000 for the six-month period ended June 30, 2022, research and development expenses for the three- and six-month period ended June 30, 2022 were $5.0 million and $10.2 million.

General and Administrative Expenses: General and administrative expenses were $3.8 million and $7.4 million for the three- and six-month period ended June 30, 2022 compared to $2.0 million and $4.0 million for the comparable periods in 2021. The increase was primarily due to higher insurance costs, personnel-related costs and professional consulting fees associated with operating as a public company. Excluding stock-based compensation expense of $381,000 for the three-month period ended June 30, 2022, and $730,000 for the six-month period ended June 30, 2022, general and administrative expenses for the three- and six-month period ended June 30, 2022 were $3.4 million and $6.6 million.

Total Operating Expenses: Total operating expenses were $8.8 million and $17.8 million for the three- and six-month period ended June 30, 2022 compared to $5.3 million and $10.0 million for the comparable periods in 2021. The increase was primarily due to increased personnel-related costs and research and development activities and resulting expenses as well as increased operating expenses associated with being a public company. Excluding stock-based compensation expense of $438,000 for the three-month period ended June 30, 2022, and $929,000 for the six-month period ended June 30, 2022, total operating expenses for the three- and six-month period ended June 30, 2022 were $8.3 million and $16.9 million.

Net Loss: Net loss was $4.1 million and $5.0 million for the three- and six-month period ended June 30, 2022, as compared to $17.1 million and $21.6 million for the comparable periods in 2021. The net loss for the three- and six-month period ended June 30, 2022 includes a non-cash credit of $5.0 million and $13.3 million, and the net loss for the three- and six-month period ended June 30, 2021 includes a non-cash charge of $12.4 million for the change in the fair value of the Company’s warrant liability, and includes stock-based compensation expense of $438,000 and $929,000 for the three- and six-month period ended June 30, 2022, and $1.1 million and $1.5 million for the three- and six-month period ended June 30, 2021. Excluding non-cash credits for the changes in the warrant liability and charges for stock-based compensation, the net loss for the three- and six-month period ended June 30, 2022 was $8.7 million and $17.4 million, as compared to $3.6 million and $7.7 million for the comparable periods in 2021.